Gout Itsnotall Crystal Clear

7/31/2019 Gout Itsnotall Crystal Clear

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Gout:

Its not all crystal clear

Robert L. Wortmann, M.D.

Department of Internal MedicineThe University of Oklahoma College of Medicine, Tulsa


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But it should be!!!!!!!!

Name another disease that

-the cause and pathophysiology are so

well undeerstood-the diagnosis can be made with

such certainty

-available therapies can be soeffective


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Objectives

Review the clinical features of gout

Review the rationale for therapies of gouty

arthritis and the underlying hyperuricemia

Answer questions


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Clinical Features of Gout

1. Hyperuricemia

2. Acute Monoarticular Arthritis

3. Tophi and Chronic Arthritis

4. Nephrolithiasis


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Clinical Course of Classic Gout


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Stage I

Asymptomatic Hyperuricemia

Serum Urate > 7.0 mg/dl


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Prevalence of Hyperuricemia

Adult Males

U.S.

France

5%

17%

Hospitalized Males

Los Angeles VA

Milwaukee VA

13%

21%


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Factors Considered in Therapy

of Asymptomatic Hyperuricemia

1. Renal Disease

2. Framingham3. SMA-12 Autoanalyzer

4. Antihyperuricemic Medications


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Is Hyperuricemia a risk factor

for coronary artery disease? Hyperuricemia is a common feature of the

Metabolic Syndrome

Epidemiologic studies are mixed andconfusing

Richard Johnsons rat model of

hyperuricemia


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Management of Asymptomatic

Hyperuricemia Determine the cause

Address contributing factors

Hypertension Obesity

Alcoholism

Hyperlipidemia At this time, specific urate-lowering drugs are not

indicated


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Stage II

Acute Gouty Arthritis

Intercritical Gout


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Overall Gout Prevalence Among All

Enrollees 1990-1999

J Rheumatol Aug 2004


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Annual Gout Prevalence Among All

Enrollees by Age Group 1990-1999

J Rheumatol Aug 2004


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Therapy for Acute Gouty

Arthritis Colchicine

Oral

IV Nonsteroidal Anti-inflammatory Agents

Corticosteroids

Intra-articular IM (ACTH)

PO


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Drug Actions In Acute Gout

Colchicine inhibits

E-selectin mediated PMN adhesion

PMN L-selectin expression

Il-1 expression

Il-8 production

PMN motility

Chemotaxis


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Drug Actions In Acute Gout

NSAIDs

Inhibits PGE2

Corticosteroids Inhibit PGE2 and LTB4

Stabilize lysosomal membranes

ACTH Agonist of the leukocyte melatonin

receptor-3


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The secret is not what isused, but how quickly

therapy is initiated afterthe attack begins!


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Stage III

Chronic Gouty Arthritis

Tophi on physical exam

Chronic degenerative arthritis


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Antihyperuricemic Therapy

1. Treat acute attack until resolved

2. Colchicine or NSAID for prophylaxis

3. Xanthine oxidase inhibitor or uricosuric

4. Address other problems

Hypertension

Obesity

Alcoholism


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Goal of Antihyperuricemic

Therapy Serum Urate 5.0 mg/dl!

Lowering serum urate to >7.0 mg/dl does not reverse

the problem. It only slowsthe rate of progression.


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TOPHI MEAN SERUM URATE

Reduced 6.2 mg/dl

Increased 8.2 mg/dl

McCarthy, Wortmann. Arthritis Rheum 1991; 34:1489.


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Candidates for Uricosuric

Agents Compliant patients

Under 60 years old

Good renal function* No ASA

Can use 81 mg but sould be taken 6 hours after

the uricosuric

No history of kidney stones

Underexcrete uric acid


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Candidates for Allopurinol

Everyone except those

Sensitive to it

Taking azathioprine

Allopurinol has

Once-a-day dosage

Few drug-drug interactions

Effective in renal failure*

Can be used in overproducers and

underproducers


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Although there have been no

new urate-lowering therapies

available to treat gout since1964, there will be soon.


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Urate-lowering Agents in

Clinical TrialsProduct Phase Mechanism

Febuxostat III NP-SIXO

Puricase II PEG urate oxidase

Uricase PEG20 I PEG urate oxidase

oxypurinol II XOIY-700 I-II XOI

KT-433 II Uricosuric


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Febuxostat

A nonpurine, selective inhibitor of xanthine oxidase in phase III studies for thetreatment of hyperuricemia in patients with gout

Current data support

Potent inhibition with significant urate reduction

Ability to administer in renal insufficiency1 and mild or moderate hepatic

insufficiency with no dosage adjustments2

Safe, effective and well tolerated in limited data of allopurinol intolerant

patients3

N

N

NH

N

OH

Allopurinol

1. Swan et al. Arthritis Rheum. 2003;48(9):S529.

2. Khosravan et al. Arthritis Rheum. 2004;50(9):S806.3. Becker et al. Arthritis Rheum. 2004;50 9 :S803.

Febuxostat

O

NC

N

CO2H

S

CH3

CH3

H3C


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Febuxostat Phase III Clinical

Trial Study design: randomized, double-blind, 52

week, multicenter trial.

Objective: to assess safety and efficacy (vs.allopurinol) of daily febuxostat

administration in lowering sUA levels in

subjects with gout and hyperuricemia (sUA

8.0 mg/dL).

Enrollment: N=760 subjects

Becker et al. ACR/ARHP Program Book Supplement. 2004;L18.


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Febuxostat

Phase III Clinical Trial ResultsCompared to allopurinol, significantly more patients oneither dose of febuxostat were able to achieve mean serum

urate concentrations less than 6.0 mg/dL

Febuxostat

80 mg

Febuxostat

120 mg

Allopurinol

300 mg

Last 3 sUA


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Why do people still suffer from

gout?

Despite the fact that we understand its cause

and underlying pathophysiology Despite the fact that we can diagnosis it

with absolute certainty

Despite the fact that we have such rationaland effective therapies


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Treatment Failures

Poor prescription

Poor compliance


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Inadequacy of Allopurinol at a dose

300 mg/day Ann Rheum Disease 1998

47%

J Rheumatol 2001

66%

N Engl J Med in press

61-79%


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Gout is Like Matches

NSAIDputs out the fire

Colchicine prophylaxiskeeps matches

damp Xanthine oxidase inhibitors and uricosurics

removes the matches


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Gout Itsnotall Crystal Clear

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